EP1196160B1 - A synergistic combination: gabapentin and pregabalin - Google Patents

A synergistic combination: gabapentin and pregabalin Download PDF

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Publication number
EP1196160B1
EP1196160B1 EP00943001A EP00943001A EP1196160B1 EP 1196160 B1 EP1196160 B1 EP 1196160B1 EP 00943001 A EP00943001 A EP 00943001A EP 00943001 A EP00943001 A EP 00943001A EP 1196160 B1 EP1196160 B1 EP 1196160B1
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EP
European Patent Office
Prior art keywords
gabapentin
pregabalin
pain
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP00943001A
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German (de)
English (en)
French (fr)
Other versions
EP1196160A1 (en
Inventor
Roger N. Brummel
Lakhbir Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
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Warner Lambert Co LLC
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Publication of EP1196160A1 publication Critical patent/EP1196160A1/en
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Publication of EP1196160B1 publication Critical patent/EP1196160B1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • R 1 is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms;
  • R 2 is hydrogen or methyl;
  • R 3 is hydrogen, or carboxyl are known in United States Patent Number 5,563,175 and its various divisionals.
  • the instant invention is a pharmaceutical composition of synergistic effect which comprises a therapeutically effective amount of gabapentin or a pharmaceutically acceptable salt or hydrate thereof and therapeutically effective amount of pregabalin or a pharmaceutically acceptable salt or hydrate thereof, with the proviso that said pharmaceutical does not contain a sodium channel blocker, or gabapentin/pregabalin/ opioid, gabapentin/pregabalin/NSAID, gabapentin/pregabalin/naproxen.
  • the pharmaceutical composition comprises gabapentin in the form of the free acid and pregabalin is in the form of the free acid.
  • the pharmaceutical composition is gabapentin in a ratio of 1:1000 and pregabalin is from 1:1000.
  • the pharmaceutical composition with a ratio of gabapentin to pregabalin from 1:1 to 1000:1 1 by weight.
  • the preferred pharmaceutical composition with a ratio from 1:1 1 to 250:1 by weight.
  • the invention is the manufacture of a medicament for the treatment of pain in a mammal in need thereof comprising administering a therapeutically effective amount of gabapentin or a pharmaceutically acceptable salt or hydrate thereof and a therapeutically effective amount of pregabalin or a pharmaceutically acceptable salt or hydrate thereof in unit dosage form, with the proviso that said pharmaceutical does not contain a sodium channel blocker, or gabapentin/pregabalin/ opioid, gabapentin/pregabalin/NSAID, gabapentin/pregabalin/naproxen.
  • a medicament for the treatment of pain in a mammal in need thereof comprising concomitant administration of gabapentin or a pharmaceutically acceptable salt or hydrate thereof and pregabalin or a pharmaceutically acceptable salt or hydrate thereof, with the proviso that said pharmaceutical does not contain a sodium channel blocker, or gabapentin/pregabalin/ opioid, gabapentin/pregabalin/NSAID, gabapentin/pregabalin/naproxen.
  • the method comprising administering gabapentin in the amount of from 5 to 250 mg and pregabalin in the amount of from 5 to 25 mg.
  • the range of the types of pain is wide including chronic and acute types.
  • Gabapentin is the generic name for the marketed product Neurontin®.
  • the chemical name is 1-(aminomethyl)-cyclohexaneacetic acid.
  • the chemical structure of the compound is:
  • Pregabalin is the generic name for (S)-3-(aminomethyl)-5-methylhexanoic acid.
  • the chemical structure of the compound is: It is also known as CI-1008 and as S-(+)-3-IBG.
  • the present invention relates to pharmaceutical compositions. These compositions have a synergistic effect in the treatment of pain. Advantages of these compositions include fewer side effects as lower dosages are needed. This increases patient compliance with the beneficial result of better control of pain.
  • the drugs can be administered together in the same dosage unit or can be prepared in separate dosage units administered at the same time. Different forms of dosage units can be used, i.e., a tablet of gabapentin and an injection of pregabalin.
  • One particular advantage of the instant invention is the fact that no cross tolerance between the two compounds has been observed.
  • the synergistic composition of this invention utilizes any GABA analogs.
  • a GABA analog is a compound derived from or based upon gamma-aminobutyric acid.
  • Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Italy) following a modified method of Hargreaves K., Dubner R., Brown F., Flores C., and Joris J., A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia, Pain 1988;32:77-88.
  • Male Sprague-Dawley rats (70-90 g) were habituated to the apparatus which consisted of three individual perspex boxes on an elevated glass table.
  • a mobile radiant heat source located under the table was focused onto the desired paw and withdrawal latencies (PWL) recorded. PWLs were taken 3 times for both hind paws of each animal, the mean of which represented baselines for right and left hind paws.
  • Gabapentin and pregabalin were synthesised at Parke-Davis (Ann Arbor, USA). ⁇ -Carrageenan were obtained from Sigma (Poole, UK). All compounds were dissolved in water except carrageenan which was dissolved in isotonic saline. Gabapentin and pregabalin combinations were administered in the same solution. Drug administrations were made in a volume of 1 mL/kg.
  • the figures show the synergy between gabapentin and pregabalin by comparing the theoretical addition and the synergetic responses.
  • Dose response data for gabapentin and pregabalin alone (a).
  • Fixed dose ratio of 1:1 gabapentin:pregabalin combination (b).
  • the theoretical additive line was calculated from the dose response data in (a). All compounds were administered P.O. and PWL to plantar test were examined 1-hour post drug administration. Results are expressed as mean PWL(s) (vertical bars represent ⁇ SEM).
  • Dose response data for gabapentin and pregabalin alone (a).
  • Fixed dose ratio of 10:1 gabapentin:pregabalin combination (b).
  • Theoretical additive line was calculated from the dose response data in (a). All compounds were administered P.O. and PWL to plantar test were examined 1-hour post-drug administration. Results are expressed a mean PWL(s) (vertical bars represent ⁇ SEM).
  • the instant invention is useful in a range of types of pain. It refers to acute as well as chronic pain.
  • Acute pain is usually short-lived (e.g. postoperative pain).
  • Chronic pain is usually defined as pain persisting from 3 to 6 months and includes somatogenic pains and psychogenic pains.
  • Other types of pain are caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.
  • Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies.
  • Psychogenic pain is that which occurs without an organic origin such as low back pain, atypical facial pain, and chronic headache.
  • inflammatory pain osteoarthritic pain
  • trigeminal neuralgia cancer pain
  • diabetic neuropathy restless leg syndrome
  • acute herpetic and postherpetic neuralgia causalgia
  • brachial plexus avulsion occipital neuralgia
  • gout phantom limb
  • bum and other forms of neuralgia, neuropathic and idiopathic pain syndrome.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied within wide limits. For practical purposes, it is present in a concentration of about 10% in a solid composition and about 2% in a primary liquid composition. In medical use the drug may be administered 1 to 3 times daily as, for example, as capsules.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 1000 mg/kg daily.
  • a daily dose range of about 1 mg to about 500 mg/kg is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the relative amounts of the active ingredients in the combination may vary within a wide range.
  • the synergistic combination may contain a ratio of about 1:1 to about 1000:1; preferably 1:1 to 500:1 and particularly from 1:1 to 250:1 parts by weight of gabapentin or a pharmaceutically acceptable salt or hydrate thereof to pregabalin or a pharmaceutically acceptable salt or hydrate thereof.
  • compositions of the instant invention are prepared by methods known in the pharmaceutical industry.
  • the compositions may be prepared by admixing the active ingredient with inert, non-toxic carriers or diluents (e.g. cellulose, silicic acid, stearine, polyomyspyrsolidone, talc, starch, etc.).
  • the compositions may also contain well known additives (e.g. emulsifying or suspending agents, dyes, salts for controlling the osmotic pressure, buffers, etc.)
  • the compound or a suitable salt thereof is dissolved in water and passed through a 0.2-micron filter. Aliquots of the filtered solution are added to ampoules or vials, sealed and sterilized.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP00943001A 1999-07-02 2000-06-21 A synergistic combination: gabapentin and pregabalin Expired - Lifetime EP1196160B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14221599P 1999-07-02 1999-07-02
US142215P 1999-07-02
PCT/US2000/017039 WO2001001983A1 (en) 1999-07-02 2000-06-21 A synergistic combination: gabapentin and pregabalin

Publications (2)

Publication Number Publication Date
EP1196160A1 EP1196160A1 (en) 2002-04-17
EP1196160B1 true EP1196160B1 (en) 2005-12-21

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EP00943001A Expired - Lifetime EP1196160B1 (en) 1999-07-02 2000-06-21 A synergistic combination: gabapentin and pregabalin

Country Status (14)

Country Link
EP (1) EP1196160B1 (es)
JP (1) JP2003503453A (es)
AR (1) AR030024A1 (es)
AT (1) ATE313322T1 (es)
AU (1) AU5753900A (es)
BR (1) BR0012058A (es)
CA (1) CA2373953A1 (es)
CO (1) CO5210869A1 (es)
DE (1) DE60024995T2 (es)
ES (1) ES2255500T3 (es)
MX (1) MXPA02000170A (es)
PE (1) PE20010331A1 (es)
UY (1) UY26230A1 (es)
WO (1) WO2001001983A1 (es)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1094757C (zh) 1996-07-24 2002-11-27 沃尼尔·朗伯公司 用于治疗疼痛的异丁基γ－氨基丁酸及其衍生物
JP4428053B2 (ja) * 2002-02-05 2010-03-10 味の素株式会社 ガバペンチン若しくはプレガバリンおよびｎ型カルシウムチャンネル拮抗剤を含有する医薬組成物
US7687080B2 (en) * 2002-11-25 2010-03-30 Taraxos Inc. Treatment of neuropathy
WO2004084880A1 (en) * 2003-03-21 2004-10-07 Dynogen Pharmaceuticals, Inc. METHODS FOR TREATING PAIN USING SMOOTH MUSCLE MODULATORS AND α2δ SUBUNIT CALCIUM CHANNEL MODULATORS
WO2004084881A1 (en) * 2003-03-21 2004-10-07 Dynogen Pharmaceuticals, Inc. METHODS FOR TREATING FUNCTIONAL BOWEL DISORDERS USING α2δ SUBUNIT CALCIUM CHANNEL MODULATORS WITH SMOOTH MUSCLE MODULATORS
PL378583A1 (pl) * 2003-03-21 2006-05-02 Dynogen Pharmaceuticals, Inc. Sposoby leczenia zaburzeń dolnych dróg układu moczowego z zastosowaniem modulatorów mięśni gładkich i modulatorów podjednostki Ó2Ű kanałów wapniowych
JP2005060311A (ja) * 2003-08-13 2005-03-10 Mochida Pharmaceut Co Ltd Ｎ−（ベンゾイル）アミノ酸誘導体を有効成分とするニューロパシー性疼痛治療剤
DE102007019071A1 (de) * 2007-04-23 2008-10-30 Ratiopharm Gmbh Stabilisierte pharmazeutische Zusammensetzung enthaltend Pregabalin
AU2009296457A1 (en) 2008-09-27 2010-04-01 Taraxos Inc. Topical formulations for treatment of neuropathy
WO2010115612A2 (en) * 2009-04-10 2010-10-14 Synthon B.V. Pregabalin compositions
BR122021013836B1 (pt) 2009-12-04 2022-05-24 Sunovion Pharmaceuticals, Inc. Composto e seu uso, composição farmacêutica

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053225A1 (en) * 1999-03-10 2000-09-14 Warner-Lambert Company Analgesic compositions comprising anti-epileptic compounds and methods of using same

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU9019198A (en) * 1997-08-19 1999-03-08 Warner-Lambert Company Methods for treating physiological conditions associated with the use, or sequelae of use, of cocaine or other psychomotor stimulants
DE19802327A1 (de) * 1998-01-23 1999-07-29 Goedecke Ag Synergistische Arzneimittelzubereitung mit analgetischer Wirkung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000053225A1 (en) * 1999-03-10 2000-09-14 Warner-Lambert Company Analgesic compositions comprising anti-epileptic compounds and methods of using same

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Publication number Publication date
AR030024A1 (es) 2003-08-13
CA2373953A1 (en) 2001-01-11
CO5210869A1 (es) 2002-10-30
MXPA02000170A (es) 2002-07-02
ATE313322T1 (de) 2006-01-15
EP1196160A1 (en) 2002-04-17
DE60024995D1 (de) 2006-01-26
DE60024995T2 (de) 2006-06-22
ES2255500T3 (es) 2006-07-01
WO2001001983A1 (en) 2001-01-11
UY26230A1 (es) 2001-03-16
BR0012058A (pt) 2002-05-14
PE20010331A1 (es) 2001-03-22
JP2003503453A (ja) 2003-01-28
AU5753900A (en) 2001-01-22

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